The present invention concerns a novel, improved method for the synthesis of 3R-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyc lohexanol, a chiral compound having valuable central nervous system (CNS) activity, particularly as an analgesic and as an antiemetic. The starting materials for this convenient and efficient synthetic method are racemic endo- and exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acids. The latter compounds are readily synthesized from the corresponding methyl esters, commercially available as a mixture of the endo and exo isomers.
3R-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohe xanol has been previously described as the highly active levorotatory isomer (enantiomer A) of cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-hydroxypropyl)cy clohexanol in Johnson et al., U.S. Pat. No. 4,371,720, which fully discloses how to use that compound, hereinafter referred to as CP-55,940.
Heretofore, CP-55,940 was synthesized from 3-ethoxy-2-cyclohexenone by one or the other of the following routes, where R.sup.a =--CH.sub.2 CH.dbd.CH.sub.2 or --(CH.sub.2).sub.3 OCH.sub.2 C.sub.6 H.sub.5 and R.sup.b = ##STR1## Either synthetic route requires many chemical steps, with resultant low over-all yields. Because resolution to the desired enantiomer occurs very late in the synthesis, these earlier processes are particularly wasteful.
The present invention includes as one step in the process, an unusual rearrangement of a chiral (C.sub.1 -C.sub.3)alkyl 1-hydroxybicyclo[2.2.2]oct-5-en-2-carboxylate to a chiral 4-(2-carbalkoxyethyl)-2-cyclohexenone. Birch et al. have previously described a somewhat related rearrangement of racemic methyl 1-hydroxy-4-methylbicyclo[2.2.2]oct-5-ene-2-carboxylate into 4-(2-carbethoxyethyl)-4-methyl-2-cyclohexenone, J. Chem. Soc. (C), pp. 125-126 (1967).
The present invention also encompasses specific chiral compounds of the formulae (10) and (11) below. These compounds are generally disclosed, without reference to chirality or to their use as intermediates, in the above referenced Johnson et al. U.S. Patent.